diabetes insipidus, nephrogenic, X-linked

Summary

diabetes insipidus, nephrogenic, X-linked (MONDO:0010581) is a disease caused by AVPR2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: AVPR2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 144

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diabetes insipidus, nephrogenic, X-linked
Mondo ID	MONDO:0010581
OMIM	304800
DOID	DOID:0081060
UMLS	C1563705
MedGen	288785
GARD	0015289
Is cancer (heuristic)	no

Also known as: diabetes insipidus, nephrogenic, 1, X-linked recessive · diabetes insipidus, nephrogenic, X-linked

Data availability: 144 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › diabetes insipidus, nephrogenic, X-linked

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

144 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 30 pathogenic, 17 likely pathogenic, 17 benign, 16 conflicting classifications of pathogenicity, 12 benign/likely benign, 7 pathogenic/likely pathogenic, 6 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4077392	NC_000023.11:g.153902531_153911235del	ARHGAP4	Pathogenic	criteria provided, single submitter
10835	NM_000054.7(AVPR2):c.738del (p.Arg247fs)	AVPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
10836	NM_000054.7(AVPR2):c.395C>A (p.Ala132Asp)	AVPR2	Pathogenic	no assertion criteria provided
10837	NM_000054.7(AVPR2):c.553G>T (p.Gly185Cys)	AVPR2	Pathogenic	no assertion criteria provided
10838	NM_000054.7(AVPR2):c.614A>G (p.Tyr205Cys)	AVPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10840	NM_000054.7(AVPR2):c.337C>T (p.Arg113Trp)	AVPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
10841	NM_000054.7(AVPR2):c.682_683insC (p.Ile228fs)	AVPR2	Pathogenic	no assertion criteria provided
10842	NM_000054.7(AVPR2):c.213G>A (p.Trp71Ter)	AVPR2	Pathogenic	criteria provided, single submitter
10843	NM_000054.7(AVPR2):c.839A>G (p.Tyr280Cys)	AVPR2	Pathogenic	criteria provided, single submitter
10844	NM_000054.7(AVPR2):c.1009C>T (p.Arg337Ter)	AVPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
10845	NM_000054.7(AVPR2):c.253G>A (p.Asp85Asn)	AVPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
10846	NM_000054.7(AVPR2):c.602G>A (p.Gly201Asp)	AVPR2	Pathogenic	no assertion criteria provided
10847	NM_000054.7(AVPR2):c.738dup (p.Arg247fs)	AVPR2	Pathogenic	no assertion criteria provided
10848	NM_000054.7(AVPR2):c.102del (p.Leu35fs)	AVPR2	Pathogenic	no assertion criteria provided
10849	NM_000054.7(AVPR2):c.410G>A (p.Arg137His)	AVPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
10850	NM_000054.7(AVPR2):c.541C>T (p.Arg181Cys)	AVPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
10851	NM_000054.7(AVPR2):c.313T>G (p.Phe105Val)	AVPR2	Pathogenic	no assertion criteria provided
10852	NM_000054.7(AVPR2):c.137T>A (p.Ile46Lys)	AVPR2	Pathogenic	no assertion criteria provided
1203715	NM_000054.7(AVPR2):c.604C>T (p.Arg202Cys)	AVPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204318	NM_000054.7(AVPR2):c.388A>T (p.Ile130Phe)	AVPR2	Pathogenic	no assertion criteria provided
2572644	NM_000054.7(AVPR2):c.468G>A (p.Trp156Ter)	AVPR2	Pathogenic	criteria provided, single submitter
2577986	NM_000054.7(AVPR2):c.262G>A (p.Val88Met)	AVPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
267269	NM_000054.7(AVPR2):c.966del (p.Trp323fs)	AVPR2	Pathogenic	no assertion criteria provided
2737425	NM_000054.7(AVPR2):c.130C>T (p.Leu44Phe)	AVPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3066243	NM_000054.7(AVPR2):c.342del (p.Ala114_Val115insTer)	AVPR2	Pathogenic	criteria provided, single submitter
3382215	NM_000054.7(AVPR2):c.135_136del (p.Ile46fs)	AVPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
3775465	NM_000054.7(AVPR2):c.614_615del (p.Tyr205fs)	AVPR2	Pathogenic	criteria provided, single submitter
424624	NM_000054.7(AVPR2):c.878G>A (p.Trp293Ter)	AVPR2	Pathogenic	criteria provided, single submitter
438660	NM_000054.7(AVPR2):c.24del (p.Ala9fs)	AVPR2	Pathogenic	no assertion criteria provided
4819422	NM_000054.7(AVPR2):c.964C>T (p.Pro322Ser)	AVPR2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
AVPR2	Definitive	X-linked	diabetes insipidus, nephrogenic, X-linked	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AVPR2	Orphanet:223	Arginine vasopressin resistance
AVPR2	Orphanet:93606	Nephrogenic syndrome of inappropriate antidiuresis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AVPR2	HGNC:897	ENSG00000126895	P30518	Vasopressin V2 receptor	gencc,clinvar
ARHGAP4	HGNC:674	ENSG00000089820	P98171	Rho GTPase-activating protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AVPR2	Vasopressin V2 receptor	G-protein-coupled receptor for arginine vasopressin, an antidiuretic that promotes renal water reabsorption.
ARHGAP4	Rho GTPase-activating protein 4	Inhibitory effect on stress fiber organization.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
GPCR	1	12.0×	0.112
Scaffold/PPI	1	8.6×	0.112

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AVPR2	GPCR	yes		Vprsn_rcpt_V2, GPCR_Rhodpsn, Vasoprsn_rcpt
ARHGAP4	Scaffold/PPI	no		RhoGAP_dom, FCH_dom, SH3_domain

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
olfactory bulb	1
type B pancreatic cell	1
granulocyte	1
monocyte	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AVPR2	146		yes	apex of heart, type B pancreatic cell, olfactory bulb
ARHGAP4	229	broad	marker	granulocyte, spleen, monocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AVPR2	1,734
ARHGAP4	1,088

Intra-cohort edges

A	B	Sources
ARHGAP4	AVPR2	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AVPR2	P30518	42
ARHGAP4	P98171	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI)	1	2855.0×	0.003	AVPR2
Vasopressin-like receptors	1	951.7×	0.005	AVPR2
Vasopressin regulates renal water homeostasis via Aquaporins	1	132.8×	0.023	AVPR2
Cargo recognition for clathrin-mediated endocytosis	1	52.4×	0.031	AVPR2
Clathrin-mediated endocytosis	1	42.6×	0.031	AVPR2
RHOA GTPase cycle	1	37.3×	0.031	ARHGAP4
G alpha (s) signalling events	1	36.6×	0.031	AVPR2
CDC42 GTPase cycle	1	36.1×	0.031	ARHGAP4
RAC1 GTPase cycle	1	30.5×	0.032	ARHGAP4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
renal water retention	1	8426.0×	0.003	AVPR2
regulation of systemic arterial blood pressure by vasopressin	1	1685.2×	0.006	AVPR2
renal water absorption	1	1203.7×	0.006	AVPR2
hemostasis	1	842.6×	0.006	AVPR2
negative regulation of fibroblast migration	1	766.0×	0.006	ARHGAP4
positive regulation of systemic arterial blood pressure	1	702.2×	0.006	AVPR2
activation of adenylate cyclase activity	1	561.7×	0.006	AVPR2
telencephalon development	1	495.6×	0.006	AVPR2
negative regulation of axon extension	1	366.4×	0.007	ARHGAP4
regulation of synapse assembly	1	351.1×	0.007	ARHGAP4
positive regulation of intracellular signal transduction	1	324.1×	0.007	AVPR2
positive regulation of vasoconstriction	1	300.9×	0.007	AVPR2
cellular response to hormone stimulus	1	191.5×	0.010	AVPR2
response to cytokine	1	187.2×	0.010	AVPR2
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	168.5×	0.010	AVPR2
Rho protein signal transduction	1	123.9×	0.013	ARHGAP4
regulation of small GTPase mediated signal transduction	1	72.0×	0.020	ARHGAP4
cytoskeleton organization	1	66.3×	0.021	ARHGAP4
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	56.5×	0.022	AVPR2
negative regulation of cell migration	1	55.8×	0.022	ARHGAP4
nervous system development	1	23.0×	0.051	ARHGAP4
negative regulation of cell population proliferation	1	21.1×	0.053	AVPR2
positive regulation of gene expression	1	19.4×	0.055	AVPR2
G protein-coupled receptor signaling pathway	1	18.1×	0.057	AVPR2
positive regulation of cell population proliferation	1	16.8×	0.059	AVPR2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
AVPR2	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AVPR2	51	4
ARHGAP4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	AVPR2
AMOXAPINE	4	AVPR2
THIOTHIXENE	4	AVPR2
CINACALCET	4	AVPR2
PYRVINIUM	4	AVPR2
BALSALAZIDE	4	AVPR2
IPRINDOLE	4	AVPR2
SERTINDOLE	4	AVPR2
NITAZOXANIDE	4	AVPR2
PIMOZIDE	4	AVPR2
DESMOPRESSIN	4	AVPR2
RIFAXIMIN	4	AVPR2
TERFENADINE	4	AVPR2
CONIVAPTAN	4	AVPR2
NERATINIB	4	AVPR2
IDEBENONE	4	AVPR2
BOSUTINIB	4	AVPR2
LASOFOXIFENE	4	AVPR2
CARBETOCIN	4	AVPR2
TOLVAPTAN	4	AVPR2
VASOPRESSIN	4	AVPR2
RIFAMPIN	4	AVPR2
ATOSIBAN	4	AVPR2
OXYTOCIN	4	AVPR2
MEFLOQUINE	4	AVPR2
MOZAVAPTAN	4	AVPR2
TRIFLUOPERAZINE	4	AVPR2
NEBIVOLOL	4	AVPR2
FLUSPIRILENE	4	AVPR2
SUNITINIB	4	AVPR2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AVPR2	309	Binding:208, Functional:100, ADMET:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
AVPR2	309

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CLOTRIMAZOLE	4	AVPR2
AMOXAPINE	4	AVPR2
THIOTHIXENE	4	AVPR2
CINACALCET	4	AVPR2
PYRVINIUM	4	AVPR2
BALSALAZIDE	4	AVPR2
IPRINDOLE	4	AVPR2
SERTINDOLE	4	AVPR2
NITAZOXANIDE	4	AVPR2
PIMOZIDE	4	AVPR2
DESMOPRESSIN	4	AVPR2
RIFAXIMIN	4	AVPR2
TERFENADINE	4	AVPR2
CONIVAPTAN	4	AVPR2
NERATINIB	4	AVPR2
IDEBENONE	4	AVPR2
BOSUTINIB	4	AVPR2
LASOFOXIFENE	4	AVPR2
CARBETOCIN	4	AVPR2
TOLVAPTAN	4	AVPR2
VASOPRESSIN	4	AVPR2
RIFAMPIN	4	AVPR2
ATOSIBAN	4	AVPR2
OXYTOCIN	4	AVPR2
MEFLOQUINE	4	AVPR2
MOZAVAPTAN	4	AVPR2
TRIFLUOPERAZINE	4	AVPR2
NEBIVOLOL	4	AVPR2
FLUSPIRILENE	4	AVPR2
SUNITINIB	4	AVPR2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	AVPR2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ARHGAP4

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ARHGAP4	0	AVPR2

Clinical trials & evidence

Clinical trials

Clinical trials: 0.